Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings

ABSTRACT

A sustained release formulation for opioid drugs is described. The formulation contains an opioid-ion exchange resin complex having a hybrid coating. The hybrid coating contains a cured polyvinylacetate polymer and a pH-dependent enteric coating layer mixed therein. Also provided are methods of making and using same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/154,970, filed May 28, 2008, which is an application that claims thebenefit under 35 USC 119(e) of U.S. Provisional Patent Application No.60/941,169, filed May 31, 2007, now expired.

BACKGROUND OF THE INVENTION

Opioids are commonly prescribed because of their effective analgesic, orpain-relieving, properties. Medications that fall within this class,referred to as prescription narcotics, include morphine sulfate (e.g.,Kadian®, Avinza™), codeine salts, oxycodone HCl (e.g., OxyContin™,Percodan™, Percocet™), and related drugs. For example, OxyContin™tablets are presently commercially available in 10, 20, 40, 80, and 160milligrams forms. Morphine, for example, is often used before and aftersurgical procedures to alleviate severe pain. Codeine, on the otherhand, is often prescribed for mild pain. In addition to theirpain-relieving properties, some of these drugs can be used to relievecoughs and diarrhea. Codeine and diphenoxylate (Lomotil™) are examplesof such drugs. However, opioid drugs are at times associated with sideeffects including, e.g., stomach upset and other gastrointestinaleffects. Further, because of the sometimes addictive properties of thesedrugs and the euphoria which can be associated with taking them,including through routes other than those prescribed, these opioid drugsare particular susceptible to abuse.

In order to reduce some of the gastrointestinal effects of these drugs,sustained release dosage forms have been described. For example, asustained-release dosage form for morphine sulfate has been described[WO 2006/124898], in which a morphine sulfate core is coated with amatrix polymer insoluble at pH 1 to 7.5, an enteric polymer soluble atpH 6 to 7.5, and an acid soluble polymer which is soluble at pH 1 to 4,and having a ratio of acid soluble polymer to enteric polymer of 1.45:1to 2.5:1 on a weight basis. Certain sustained release formulations arecommercially available under the trademark Kadian® and are currentlyavailable in 20, 30, 50, 60 and 100 mg capsules.

Attempts to reduce abuse of opioid by pharmacological methods have beenmade. One such attempt involves including an “opioid antagonist” alongwith the opioid “agonist”. These antagonists cannot be easily extractedfrom the agonist and will cause an aversive effect in a physicallydependent patient. However, these antagonists may have other sideeffects which may be disadvantageous.

One attempt to reduce opioid abuse and avoid the use of anagonist-antagonist combination has been described in US 2005/0163856A1,published Jul. 28, 2005. This patent application describes an oxycodoneformulation designed to provide a pH independent release rate with apeak plasma level between 5-6 hours after administration. Theformulation provides an oxycodone mixed with 40-65 wt % matrix formingpolymer and 5 to 15 wt % of an ion exchange resin.

Ion exchange resins coated with a diffusion barrier coating have beendescribed for the preparation of sustained release systems for preparingsustained release formulations. See, US-2006-0115529; WO 2006/101536; WO2005/117843; US-2005-0265955 A1; WO 01/070194; U.S. Pat. Nos. 4,221,778,4,996,047, 4,221,778 and 4,861,598. For example, U.S. Pat. No. 6,001,392granted Dec. 14, 1999 describes certain acrylate based (e.g., EUDRAGITpolymer system) and ethyl cellulose (e.g., SURELEASE, AQUACOAT) polymersfor coating a drug-ion exchange resin complex using either a solvent oraqueous based coating to achieve sustained release of the drug from thedrug-ion exchange resin complex. There appears to be no meaningful dataregarding the integrity of the coating film. Further, there is no datain the '392 patent of prolonged release of the drug from the coateddrug-ion exchange resin complex beyond about 12 hours. There have beenliterature-reported drawbacks of using ethyl cellulose based aqueousdispersions as coatings for drug-ion exchange resin complexes.

Enteric coatings have been described as delayed release polymers forproviding an initial delay in drug release. See, e.g., U.S. Pat. No.6,756,057 for amoxicillin and U.S. Pat. No. 6,555,127 formethylphenidate. Enteric coatings are also used for protecting the bodyfrom drugs which cause gastric irritation (e.g., naproxen which iscommercially available as enteric coated tablet and capsuleformulations).

US-2006-0115529 and WO 2006/101536 describe the use of film coatings fora fast melt tablet containing ion exchange resin complex particles mixedwith a dry binder and bulk diluent. One suitable coating described isthe KOLLICOAT SR30D polymer system. Optional use of an enteric coatwhich is insoluble in acidic pH and soluble in basic pH is described.

US-2004-0126428 describes a product which is described as being abuseresistant. This product contains a core comprising a resinate of anopioid formed from the drug (e.g., morphine sulfate) and an ion exchangeresin. A multi-component coating may also applied to the core, whichcontains (a) from 1 to 85% by weight of a matrix polymer which isinsoluble at a pH of from 1 to 7.5 and contributes to the control of therate of release of the active ingredient in the stomach and intestines;(b) from 1 to 30% of an enteric polymer which is substantially insolubleat a pH of from 1 to 4, sufficient to delay the release of the activeingredient in the stomach, but which is soluble at a pH of from 6 to 7.5so as not to substantially delay release in the intestines; (c) from 1to 60% of a compound soluble at a pH of from 1 to 4.

US 2003-0099711 A1 describes using an ethyl cellulose polymer in anaqueous based coating system as a barrier coating. This publicationfurther describes use of an optional enteric coating over the barriercoating to delay the drug release.

Opioid drug formulations which provide a desired sustained releaseprofile without requiring an agonist-antagonist combination to reduceabuse are desirable from a commercial drug perspective.

SUMMARY OF THE INVENTION

The present invention provides a modified release tablet formulation ofan opioid drug bound to an ion exchange resin, coated with a hybridcoating comprising a barrier coating containing a polyvinyl acetatepolymer and a plasticizer and an enteric polymer mixed therewith.

Advantageously, the combination of sustained release provided by thecomplexation of the opioid drug with the ion exchange resin and thehybrid layer coating comprising the barrier coating component and theenteric coating component, provide a desired modified release profilewhile also providing favorable abuse resistance properties.

In one embodiment, the drug-ion exchange resin complex further comprisesa solvating agent or a release retardant.

In a further embodiment, the invention provides a solid dose modifiedrelease morphine formulation. This formulation may be a tablet or acapsule containing granules of the invention and contains apharmaceutically effective amount of morphine bound to apharmaceutically acceptable cationic exchange resin complex. The complexis provided with a cured hybrid modified release coating directlythereon. The hybrid coating comprises a single cured layer comprising auniform mixture of a barrier forming component containing at least apolyvinylacetate (PVA) polymer system and a plasticizer and entericcoating forming component preferably containing at least a PVA-phthalateand at least one plasticizer.

The invention further provides a method of administering an opioid drug(e.g., morphine) for a sustained period, the method comprisingadministering a formulation of an opioid drug bound to an ion exchangeresin, coated with a hybrid coating as described herein.

Other aspects and advantages of the invention will be readily apparentfrom the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an opioid drug-ion exchange resin complexhaving a cured hybrid coating composed of a water-insoluble,water-permeable based diffusion barrier coating component and an entericcoating component. This cured, hybrid coated opioid-drug ion exchangeresin complex of the invention provides desirable modified releaseproperties while also providing desired abuse resistance.

The “barrier coating component” is a polyvinylacetate-based polymericsystem, containing a plasticizer. Polyvinyl acetate, due to its hightensile strength in the presence of a plasticizer(s), provides aflexible coating film for use as the water-permeable diffusion barriercoating that maintains its film integrity even when subjected to severephysical force and stress such as during a compression step in atabletting machine or the grinding action of a coffee beans grinder,mill, etc. As described herein, this material remains substantiallynon-tacky and process-friendly with the addition of a plasticizer duringthe coating operation in a Wurster fluid bed or other coating operationand do not cause agglomeration during the coating of very fine particlesof drug-ion exchange resins. Agglomeration (sometimes termed “caking” or“brick formation”) during a coating operation may otherwise impede theair flow, destroy flow pattern, and/or clog the spray nozzle, therebyincreasing the possibility of an imperfect and uneven coating of thedrug-ion exchange resin particles.

As used herein, the term “enteric coat component” refers to a polymersystem having pH-dependent solubility. More particularly, an entericcoat component used in the present invention is insoluble in an aqueoussystem at acidic pH, e.g., in the range typically found in the stomach,but soluble at higher pH such as are found in the lower gastrointestinaltract. In one embodiment, the enteric coat component is insoluble at pH1 to about 5.5 and soluble at a pH above about 5.5 in an aqueous system(e.g., gastric juices). Further, the enteric polymer selected for use inthe invention is compatible with the barrier coating component of thehybrid coat. More particularly, the enteric coating polymer(s) isnon-reactive with the barrier coating, i.e., does not form a gel orgel-like substance, and allows uniform application of the hybrid coatingto the resin. For example, in one embodiment, the barrier coatingcomponent is a polyvinylacetate-based polymeric system; the inventorsfound that a mixture of this polymeric system with a water insolublemethacrylic acid:acrylic acid ethylester 1:1 copolymer enteric coatingpolymers [commercially available as Eudragit™ L30 D55] reacted to form agel-like substance which could not be satisfactorily applied as acoating material. In another example, another methacrylicacid:ethylacrylic acid copolymer [commercially available as a 30%dispersion under the name Eudragit L100 55] when mixed with the barriercoating component was found to cause undesirable “clumping” or cloggingof the coating apparatus when mixed with the barrier coating componentand prevented uniform application of the hybrid coating.

One particularly suitable enteric polymer is a polyvinylacetatephthalate (PVAP) based system, which the inventors found to combine andmix well with the polyinylacetate-based barrier coating. One suchenteric polymer system is available commercially as SURETERIC™, which isdescribed in U.S. Pat. No. 5,733,575 (see, particularly example 1), thedisclosure of which is incorporated by reference herein. The '575 patentdescribes an enteric polymer system which, in one embodiment, is formedby the mixture of PVAP with a liquid plasticizer, a solid plasticizer, adetackifier and a lubricant. Suitably, the enteric polymer system alsocontains an alkalizing agent, a viscosity modifier, an anti-cakingagent, and may include an anti-foam solution to prevent foaming duringpreparation. The final enteric polymer solution is passed through a 60mesh screen. The '575 patent describes the use of titanized PVAP or jetmilled PVAP. In Example 1, titanized PVAP is utilized, which isdescribed earlier in the document as having 10% titanium dioxide mixedinto the PVAP while it is being made. The SURETERIC™ enteric dry powdercomposition is prepared as described in Example 1 of the '575 patent, bymixing the liquid plasticizer Citroflex triethylcitrate into titanizedPVAP, the alkalizing agent sodium bicarbonate, the solid plasticizerpolyethylene glycol 3350, the lubricant stearic acid, the viscositymodifier sodium alginate, and Cabosil Eh5 silica (anti-caking), andmixing in water with an antifoaming solution. Other suitable PVAPsystems useful in the invention may be designed taking intoconsideration this information and the desirable enteric polymer systemproperties described herein.

Advantageously, the hybrid coating material of the present invention issufficiently flexible that it can withstand the amount of pressureapplied during compression of the coated drug-ion exchange resinparticles into tablet or granular form. Further, following oral deliveryand after passing through the stomach and into the higher pH level ofthe lower gastrointestinal tract, the pH-dependent, water-solubleenteric polymer (e.g., PVAP based system) begins to dissolve. Thus, theenteric polymer component of the hybrid coating serves as a pH-dependentpore-former which provides initial delayed release to the dosage unit,whereas the water permeable barrier coating polymer system (polyvinylacetate-based system) continues to control release. These solid oraldose units are believed to function in a manner similar to amultiparticulate system; more particularly, the tablet or capsuledisintegrates in the stomach to release the particles (granules), whichrelease active drug evenly and reduce variability in the releaseprofile.

Thus, the drug release pattern from the compositions of the presentinvention is controlled or modified by combining at least one opioiddrug (e.g., morphine sulfate) and an ion exchange resin (e.g., acationic resin) to form the drug-resin complex prior to the applicationof the hybrid water-permeable diffusion barrier coating-enteric coatinglayer.

Optionally, other water-insoluble polymers may be included in thedrug-ion exchange resin complex, including a single polymer or mixturesthereof, such as may be selected from polymers of ethyl cellulose,polyvinyl acetate, cellulose acetate, polymers such as cellulosephthalate, acrylic based polymers and copolymers (such as, for example,those available under EUDRAGIT brand name) or any combination of suchinsoluble polymers or polymer systems herein defined as a “releaseretardant”. The drug-ion exchange resin complex with or without a“release retardant” may be formulated to achieve the desired length oftime of drug release rate from such drug-ion exchange resin complexes.Such coating systems could be further customized by the incorporation ofindividual or a combination of hydrophilic or lipophilic plasticizerswith a dispersion or suspension containing the barrier coating polymer.Such plasticizers include, e.g., propylene glycol, polyethylene glycol,triacetin, triethyl citrate, dibutyl sebacate, vegetable oil, lipids,etc.

As used herein, the term “modified release” refers to compositions ofthe invention which are characterized by having a drug release from adrug-ion exchange complex of the invention over a period of at leastabout 12 hours, and preferably up to about 24 hours. The release profilemay be assessed using in vitro dissolution assays known to those ofskill in the art [e.g., USP basket method or Paddle Method, or channelflow method]. The release profile can be assessed in vivo (e.g., forbioequivalence determinations), using plasma concentrations to assessmaximum concentration (Cmax) and area under the curve (AUC). Such assaysare well known to those of skill in the art.

For example, a modified release composition of the invention can betailored to at least essentially match the in vivo release profile of acommercially available prescription opioid modified release composition.In one embodiment, the composition of the invention is tailored to meetthe in vivo release profile of a 12 hour or 24 hour product, e.g., suchas the sustained release morphine sulfate KADIAN® morphine sulfatecapsules, Avinza® morphine sulfate, MS CONTIN® morphine sulfate or aOxyCONTIN® oxycodone product [in vivo release profiles published inproduct literature, also available from Kadian® web cite and thePhysician's Desk Reference]. See, also, U.S. Pat. Nos. 5,508,042;5,266,331; 5,549,912; 5,656,295, for a description of the releaseprofile of the Kadian® release profile. See, also, U.S. Pat. No.5,672,360.

In one embodiment, a tablet prepared from the hybrid coated ion exchangeresin complex of the invention provides an in vitro dissolution rate ofabout 5 to about 20% in 1 hour, about 30% to about 50% in 2 hours, about70% to about 85% in 4 hours, and more than 90% in 12 hours, e.g., asmeasured by the USP Paddle Method. A capsule containing granules can bedesigned to provide a similar release rate. The product is expected toprovide an in vivo therapeutic effect lasting for at least 12 up toabout 24 hours.

The term “modified release” may include, e.g., compositions which areextended release formulations (also termed “prolonged releaseformulation”), sustained release formulations, certain pulse deliverysystems, or delay release formulations.

The hybrid coated opioid-ion exchange resin complexes of the inventionand formulations (Example 2) containing the complex provide desirableabuse resistance properties. Certain commercial opioid products, such asKadian® morphine sulfate, report in its product literature that thecapsules are to be swallowed whole or sprinkled in applesauce. Thepellets in the Kadian® morphine sulfate capsule are not to be chewed,crushed or dissolved, all of which would lead to rapid release andabsorption of morphine. The OxyContin® oxycodone product literaturecontains a similar warning for its oxycodone product. The hybrid coatedopioid-ion exchange resin complex of the invention is designed toprovide an advantage in delaying release of active over products whichcould provide an almost immediate release of such active opioidingredient upon such abuse of such product.

Further properties of the hybrid coating system of the present inventionare discussed below.

As used herein in reference to numeric values provided herein, the term“about” may indicate a variability of as much as 10%.

A detailed description of the components of the compositions of thepresent invention follows.

Opioid Drugs

The formulations of the invention are particularly well suited for oraldosage units containing opioid drugs having abuse potential. In oneembodiment, these oral dosage units are solid dosage units. However,these formulations are adaptable to other types of dosage units (e.g.,suspension, etc) and other active components.

In one embodiment, the opioid drugs are used in the treatment ofrespiratory tract disorders such as, for example, antitussiveexpectorants such as dihydrocodeine phosphate, codeine phosphate, andnoscapine hydrochloride. In another embodiment, the opioid drugs areanalgesics drugs such as hydrocodone, morphine, hydromorphone,oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone,buprenorphine, fentanyl and derivatives thereof, dipipanone, tramadol,etorphine, dihydroetorphine, butorphanol, levorphanol, or salts thereofor mixtures thereof. In one embodiment, the opioid is morphine,oxycodone, hydrocodone, or a salt thereof. In one embodiment, a morphinesalt is morphine sulfate; an oxycodone salt is oxycodone HCl; and acodeine salt is codeine sulfate or phosphate.

The pharmaceutically acceptable salts include, but are not limited to,inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.Other suitable salts will be readily apparent to one of skill in theart.

In certain embodiments, the amount of the opioid drug in the compositionmay be about 1 mg to 250 mg. In another embodiment, the amount of theopioid drug in the composition is about 5 mg to about 200 mg. In stillanother embodiment, the amount of the opioid drug in the composition isabout 10 mg to about 150 mg. The preceding list is not intended to beexclusive. In some embodiments, the composition of the invention isdesigned to provide a release profile similar to a commerciallyavailable product. In such an instance, the present invention providesan equivalent amount of active opioid to the commercially availableproduct based on weight. In another embodiment, the present inventionprovides an amount of active opioid bioequivalent to the commerciallyavailable product, i.e., provides a finished formulation having an invivo release profile similar that of the commercial product. This can bereadily determined by taking into consideration the molecular weight ofthe free base of the opioid drug bound to the resin, as compared to thecompound in the commercial product, and further taking intoconsideration the percentage of active drug loaded on the resin. Thesecalculations are well within the skill of one in the art.

Ion-Exchange Resin

Ion-exchange resins suitable for use in these preparations arewater-insoluble and comprise a preferably pharmacologically inertorganic and/or inorganic matrix containing functional groups that areionic or capable of being ionized under the appropriate conditions ofpH. Typically the size of the ion-exchange particles is from about 10microns to about 420 microns, preferably the particle size is within therange of about 40 microns to about 250 microns for solid dosage forms,e.g., tablets and granules placed in capsules. Particle sizessubstantially below the lower limit are generally difficult to handle inall steps of the processing. Generally, uncoated drug-ion exchange resinparticles of the invention will tend to be at the lower end of thisrange, whereas coated drug-ion exchange resin particles of the inventionwill tend to be at the higher end of this range. However, both uncoatedand coated drug-ion exchange resin particles may be designed within thissize range. For additional discussion of ion exchange resins, see, e.g.,co-pending US Patent Publication No. US 2007-02155A1, published Sep. 20,2007, [application Ser. No. 11/724,966, filed Mar. 15, 2007, entitled“Modified release formulations containing drug-ion exchange resincomplexes”] and its international counterpart WO 2007/109104, publishedSep. 27, 2007, which are incorporated by reference.

A suitable ion exchange resin is selected depending upon the charge ofthe active opioid or its salt. For example, cation exchange resins arewell suited for use with drugs and other molecules having a cationicfunctionality, including, e.g., oxycodone, morphine, hydrocodone,oxymorphone, and hydromorphone, as well as prodrugs, salts, isomers,polymorphs, and solvates thereof. Cationic exchange resins have beendescribed in the art and also commercially available. Examples ofcommercially available cationic resins include, without limitation, DowXYS-40010.00 and Dow XYS-40013.00 (The Dow Chemical Company), AmberliteIRP-69 (an insoluble, strongly acidic, sodium polystyrene cationexchange resin), Amberlite IRP-64 (weekly acidic), Amberlite IRP-120(Rohm and Haas), Amberlite IRP-88 (weakly acidic). Amberlite IRP-69(Rohm and Haas) is sulfonated polymers composed of polystyrenecrosslinked with 8% of divinylbenzene, with an ion exchange capacity ofabout 4.5 to 5.5 meq/g of dry resin. It consists of irregularly shapedparticles with a size range of 47 to 149 microns. A series of cationicresins are also available from DOW Chemical as the DOWEX™ 50WX series(Dow Chemical Company). There are mainly four products with differentparticle size distribution: cut-off mesh size is US Sieve No. 50 (300microns) in the case of Dowex™ 50WX2-50, 100 (150 microns) in Dowex™50WX2-100, 200 (75 microns) in Dowex™ 50WX2-200, and 400 (38 microns) inDowex™ 50WX2-400. Crosslinking is another important factor, which caninfluence physical properties, equilibrium conditions, drug loading, anddrug release profiles. Resins of various degrees of permeability aredependent on the divinylbenzene content, which was described as thedegree of resin crosslinkage and the number after X is the percentage ofdivinylbenzene in the resin polymer. For example, Dowex™ 50WX2-50contains 2% divinylbenzene with particle size is bigger than 50 mesh.Total exchange capacity of 2, 4 and 8% crosslinkage resins are 0.6, 1.1and 1.7 meq/ml, respectively. Still other ion exchange resins areavailable from Sigma-Aldrich.

Both strongly acidic and weakly acidic resins (e.g., cationic resins)are commercially available and can be selected for use. However, it willbe understood that the strength of the bond between the opioid drug andthe resin will be affected by whether the resin is strongly acidic orweakly acidic. More particularly, a stronger bond will typically beformed by the strongly acidic resin and thus, drugs loaded thereon willhave a slower release profile than those loaded on a weakly acidicresin. Thus, one of skill in the art can select the desired type ofresin to achieve a desired release profile, further taking intoconsideration such factors as the use of a release retardant, thethickness of the hybrid coating, and the ratio of barrier coatingcomponent to enteric coating component.

Other suitable resins can be selected by one of skill in the art, takinginto consideration the charge of the free base or salt form of a desiredopioid drug.

The selected ion-exchange resins may be further treated by themanufacturer or the purchaser to maximize the safety for pharmaceuticaluse or for improved performance of the compositions. Impurities presentin the resins may be removed or neutralized by the use of commonchelating agents, anti-oxidants, preservatives such as disodium edetate,sodium bisulfate, and so on, by incorporating them at any stage ofpreparation either before complexation or during complexation orthereafter. These impurities along with their chelating agent to whichthey have bound may be removed before further treatment of the ionexchange resin with a release retardant and diffusion barrier coating.

Opioid Drug-Ion Exchange Resin Complexes

Binding of the selected opioid drug or a combination of drugs includingat least one opioid drug to the ion exchange resin can be accomplishedusing methods known in the art. See, e.g., co-pending US PatentPublication No. US 2007-02155A1, published Sep. 20, 2007, [applicationSer. No. 11/724,966, filed Mar. 15, 2007, entitled “Modified releaseformulations containing drug-ion exchange resin complexes”] and itsinternational counterpart WO 2007/109104, published Sep. 27, 2007, andthe documents cited therein, incorporated by reference.

The amount of drug that can be loaded onto a resin will typically rangefrom about 1% to about 75% by weight of the drug-ion exchange resinparticles. A skilled artisan with limited experimentation can determinethe optimum loading for any drug resin complex, taking into suchconsideration as the desired amount of active drug and the desired sizeof the final dose formulation. For example, to reduce the size of aformulation or to increase the amount of active drug, a higher loadingpercentage may be used. Conversely, where a lesser amount of active drugis desired, a loading percentage at the lower end of this range may beprovided. In one embodiment, loading of about 10% to about 40% byweight, more desirably, about 15% to about 30% by weight, of thedrug-ion exchange resin particles can be employed. Typical loadings ofabout 25% by weight of the drug-ion exchange resin particles can beadvantageously employed.

Thus, in one aspect, the invention provides drug-ion exchange resincomplexes comprising an opioid drug loaded in an ion exchange resin asdescribed herein. The drugs and ion exchange resins may be readilyselected from amongst those drugs and resins described herein. Theinvention further provides drug-ion exchange resin matrixes defined asfollows.

Release Retardants

The drug release rate from the compositions of the present invention maybe further prolonged or modified by treating the drug-ion exchange resincomplex prior to the application of the hybrid coating described herein,with a release retardant which is a water-insoluble polymer or acombination of a water-insoluble polymers.

Advantageously, the release retardant does not form a separate layer onthe drug-ion exchange resin complex, but forms a matrix therewith.Examples of suitable release retardants include, for example, apolyvinyl acetate polymer or a mixture of polymers containing same(e.g., KOLLICOAT SR 30D), cellulose acetates, ethylcellulose polymers(e.g., AQUACOAT™ ECD-30 or SURELEASE™), acrylic based polymers orcopolymers (e.g., represented by the EUDRAGIT family of acrylic resins),cellulose phthalate, or any combination of such water-insoluble polymersor polymer systems, all herein defined as “release retardants”. Theseretardants when used may further prolong or alter the release of thedrug from the coated drug-ion exchange resin complex and maximizeattaining the desired release profile. Further, use of a releaseretardant permits in some cases lowering the amount of coating thicknessneeded to attain a prolonged drug release of up to 24 hours. Theseretardants can be used in either substantially pure form or as acommercial preparation obtained from a vendor. The preferred releaseretardant is a polyvinyl acetate polymer system, e.g. the KOLLICOATSR30D system, as described herein or an acrylic polymer from theEUDRAGIT family. Examples of suitable acrylic polymers from the EUDRAGITfamily may include, e.g., a copolymer comprising ethyl acrylate andmethyl methacrylate (e.g., EUDRAGIT NE-30D), or EUDRAGIT RS, RL30D,RL100, or NE, which are largely pH-independent polymers; less desirable,certain pH-dependent members of the EUDRAGIT polymer family, e.g., theL, S, and E, polymers may be selected].

The quantity of polymer that is added as a release retardant typicallyranges from about 3% to about 30% or more by weight of the uncoateddrug-ion exchange resin particles. More preferably the releaseretardant, if used, is in the range from about 5% to about 20% and mostpreferably in the range of about 10% to about 15% by weight of theuncoated drug-ion exchange resin particles, depending on the nature ofthe drug-ion exchange resin complex and the desired release profile ofthe medicinal agent(s). In one embodiment, the composition of theinvention is designed to match the in vivo release profile of acommercially available drug(s).

These release retardants can be added during the formation of thedrug-ion exchange resin complex either in the beginning, during themiddle, or after substantial amount of complex formation has takenplace. In the more preferred embodiment, the retardant is added afterthe formation of drug-ion exchange resin complex. Upon mixing, thedrug-ion exchange resin complex particles with the release retardant,the mixture is dried and milled appropriately. In some cases, themilling may be carried out before the complete drying of the complex andthen again further drying followed by milling to obtain the desiredcomplex characteristics.

The release rate of the present aqueous based hybrid coating of theinvention which are designed to provide finished dosage orallyingestible pharmaceutical compositions such as tablets, capsules, etc.are tailored to provide the desired drug release profile over a periodof about 8 to 24 hours, and preferably 12 to 24 hours.

This programmable release rate may be controlled by the hybrid coatingthickness and optionally, the use of “a release retardant” component asdescribed above, added to the drug-ion exchange resin complex to form afine particulate matrix prior to the polymer film coating step. Therelease retardant is preferably a water insoluble polymer as previouslydescribed such as a PVA dispersion which has the same or similarcomposition of solids as the preferred aqueous based film formingcoating polymer dispersion described herein used in the coating step oran acrylic based polymer available commercially under the EUDRAGIT™brand name, manufactured by Degussa (previously manufactured by RohmPharma Polymers). The properties of different EUDRAGIT™ compositionscommercially available are described in literature from Degussa or RohmPharma and are also described in U.S. Pat. No. 6,419,960 (column 10-11),the disclosure of which is incorporated herein by reference. Other waterinsoluble polymers include those listed in column 10, lines 41-53 ofU.S. Pat. No. 6,419,960 the disclosure of which is incorporated hereinby reference.

Another embodiment is the use of an impregnating (solvating) agent as arelease retardant incorporated into the pharmaceutically acceptable drugion-exchange resin complex prior to addition of the aqueous basedcoating. This impregnating (solvating) agent is a hydrophilic (watersoluble) agent exemplified by those materials described for example inU.S. Pat. No. 4,221,778 and published US Patent application PublicationNo. US 2003/009971 A1, the disclosures of which are incorporated hereinby reference. Specific examples of suitable impregnating agents includepropylene glycol, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., KOLLIDON™ K30) mannitol, methyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sorbitol.

In one embodiment, the coated drug-ion exchange resin complex particlesare mixed in the presence of a granulating agent, to aid in providingparticles with a relatively even particle size range. The granulatingagent can be one or more substances that do not adversely react with theother components of the complex and/or the active ingredient(s).Suitable granulating agents include the release retardant, solvatingagent, sweetener(s) and the like.

Suitably, the resulting drug-ion exchange resin complexes are of a sizein the range of about 20 microns to 420 microns, which are predominantlyin the range of about 40 microns to about 250 microns, with particles upto about 420 micron being used for solid dosage forms, e.g., tablets andgranules in capsules. It has been found that particles above about 420microns have a somewhat undesirable mouth feel following administration.

Coating System

Suitably, the present invention provides a hybrid coating is a curedcoating composed of a water permeable, water insoluble barrier coatingcomponent comprising at least a polyvinyl acetate polymer and aplasticizer, and an enteric polymer component which is insoluble inaqueous systems at the pH of the stomach and soluble in aqueous systemsat the higher pH of the gastrointestinal tract. The water permeable,water insoluble barrier coating comprises a blend of polymers comprisinga polyvinyl acetate polymer and polyvinylpyrrolidone. The plasticizerfacilitates uniform coating of the drug-ion exchange resin complex andenhances the tensile strength of the barrier coating component and thus,the hybrid coating.

The aqueous based dispersions that are used to provide a diffusionbarrier coating component of the hybrid coating are characterized byhaving a relatively low tackiness in either the absence or presence ofplasticizer(s) and provide a high percent elongation of the polymer film(elasticity) at break in the presence or absence of plasticizer(s). Morespecifically, the polymer film coating is characterized by exhibiting atackiness as measured by the Hössel method described by P. Hössel,Cosmetics and Toiletries, 111 (8) 73 (1996) at 20° C./80% RH and 30°C./75% RH of about 2 or less in the presence or absence of a plasticizerand preferably about 0.5 or less.

The relatively low tack barrier coating component of the presentinvention provided by a polyvinyl acetate (PVA) polymer facilitates morerapid and easier processing of the coating composition and permits useof lower quantities of plasticizer. This provides for enhancedelongation (elasticity) and flexibility of the coating, a desirableproperty of the polymer without significantly increasing tackiness toundesirable levels due to use of a plasticizer.

Thus, the selection criteria for the plasticizer incorporated into theaqueous based polymer dispersion composition is to enhance highflexibility or elongation (elasticity) of the coating at break measuredby the texture analyzer TA-XT2 HiR (Stable Microsystems) and by themethod reported by the manufacturer in its literature [i.e., Jan-PeterMittwollen, Evaluation of the Mechanical Behavior of Different SustainedRelease Polymers, Business Briefing: Pharmagenerics, 2003, pp. 1-3,BASF], of at least about 100%, of at least about 125% and preferably ina range between about 150% to about 400% while not substantiallyincreasing the tackiness of the polymer film greater than about 2(wherein the film is measured by the Hössel method referenced aboveindependent of any composition on which it has been deposited). Thehigher elasticity ranges are usually achieved with coatings of thepresent invention through the use of a relatively small amount ofplasticizer. By using relatively small amount of plasticizer, theplasticizer does not achieve high enough levels to negatively effect theproperties of the coating. It has been found that these objectives areachieved by using a relatively lower percent by weight of the selectedplasticizer(s) based on the percent by weight of the solids in theaqueous based film forming polymer composition.

Generally, a plasticizer is used in the percent range, or a mixture ofplasticizers combine to total, about 2 to about 30% by weight (solidscontent) of the coating layer, more preferably about 2.5% to about 20%by weight of the coating layer on the coated drug-ion exchange resincomplex. Preferably a plasticizer in range of about 3% to about 10% byweight of the coating layer based on the coated complex providesdesirable properties. However, depending upon tabletting conditions,amounts of plasticizers in the higher end of the general range providedmay be desired (e.g., for high pressure compression).

Suitable plasticizers are either water soluble or water insoluble.Examples of suitable plasticizers include, e.g., dibutyl sebacate,propylene glycol, polyethylene glycol, polyvinyl alcohol, triethylcitrate, acetyl triethyl citrate, acetyl tributyl citrate, tributylcitrate, triacetin [a triester of glycerol and acetic acid, also knownby the chemical name 1,3-diacetyloxypropane-2-yl acetate], and Soluphor®P [2-pyrrolidone, BASF Corp], and mixtures thereof. Other plasticizersare described in patent application publication US 2003/0099711 A1, May29, 2003, page 4 (0041) the disclosure of which is incorporated hereinby reference.

The barrier coating component is an aqueous bases polyvinyl acetate(PVA) polymer based aqueous coating dispersion which is mixed with aplasticizer as described herein. The PVA is insoluble in water at roomtemperature. The PVA may be used in either substantially pure form or asa blend. A commercial blend contains primarily a polyvinyl acetatepolymer, a stabilizer, and minor amounts of a surfactant such as sodiumlauryl sulfate. More specifically, the preferred aqueous based coatingsolution is KOLLICOAT SR 30 D (BASF Corporation) and whose compositionis about 27% PVA polymer, about 2.7% polyvinylpyrrolidone (PVP), about0.3% sodium lauryl sulfate (solids content 30% w/w). See, also, U.S.Pat. No. 6,066,334, which is incorporated by reference herein. The PVPand surfactant help stabilize the aqueous dispersion of the PVA.Generally, such stabilizing components are present in an amount totalingless than about 10% w/w, and preferably less than about 5% w/w. In oneembodiment, if a substantially pure form of PVA is used, it can bedissolved in a suitable non-aqueous solvent with the enteric polymercomponent to form the hybrid coating solution for the drug ion-exchangeresin complex.

Where the hybrid coating comprises a PVA polymer in the barrier coatingcomponent, the PVA polymer is present in an amount of about 70% to about90% w/w of the barrier coating component, at least about 75%, at leastabout 80%, about 85% w/w of the barrier coating component.

Where the barrier coating component also comprises PVP as a stabilizercomponent (e.g., as is present in KOLLICOAT™ SR 30D), the barriercoating component generally contains about 5 to about 10% w/w ofpolyvinyl pyrrolidone.

As described above, the enteric coating selected for use in the presentinvention is a polymer which is insoluble at acidic pH in an aqueoussystem, e.g., in gastric juices, but soluble at higher pH such as arefound in the lower gastrointestinal tract and is non-reactive with thebarrier coating. In one embodiment, where the barrier coating comprisespolyvinylacetate, the enteric coating comprises a polyvinylacetatephthalate system.

According to the present invention, the components of the hybridcoating, including, the barrier coating polymer component and theenteric coating component are mixed in order to form a homogenousmixture of the heterogeneous components. In one embodiment, the barriercoating component and the enteric coating component are dispersed in anaqueous based system, mixing at room temperature for a sufficient periodof time to ensure uniform distribution of the component. Where anon-aqueous based system is used, a suitable solvent for both thebarrier coating component and the enteric coating component is selected.One suitable solvent system may include, e.g., methylene chloride.

In one embodiment, the hybrid coating contains about 20:1 to about 3:1,based on solids content, of barrier coating component to enteric coatingcomponent. In a further embodiment, the hybrid coating contains 10:1 to4:1, or about 6:1 to 4:1 barrier coating to enteric coating, based onsolids content.

Suitably, the hybrid coating is applied as an aqueous dispersion usingcoating techniques such as are described herein, e.g., the WURSTERprocess. Alternatively, other coating techniques which result in uniformcoating could be readily selected by one of skill in the art.

In one embodiment, the hybrid barrier coating-enteric coating is about10% to about 60%, by weight, of the uncoated drug-ion exchange resincomplex. In another embodiment, the hybrid barrier coating-entericcoating is about 25% to about 50% by weight of the uncoated drug-ionexchange resin complex, about 30% to about 45% by weight of the uncoatedcomplex, or about 35 to about 40% by weight of the uncoated drug-ionexchange resin complex.

In one embodiment, the hybrid coating is cured and comprises a polyvinylacetate polymeric barrier coating system commercially available asKOLLICOAT SR-30D, a plasticizer, and the enteric coating componentcomprising polyvinyl acetate phthalate. The coating can be cured forabout 1 to about 24 hours. Alternatively, the coating is cured for about4 to about 16 hours, and in one embodiment, at about 5 hours at hightemperature, e.g., about 50° C. to about 65° C., and preferably about60° C.

The resulting coated particles are within the size range describedherein, i.e., they are preferably below about 420 microns in size, withthe majority falling within the range of about 40 micron to about 250micron range.

Optionally, a non-functional film coating may be applied on the exteriorof the tablet, e.g., to permit application of a gloss coat or a dye.Such a non-functional coating does not affect the release profile of thedosage unit. Such a coating may be present in an amount of about 1 to10% w/w of the coated particle, and more preferably, about 1 to about 5%w/w of the coated particle. Examples of suitable coating compositionsinclude those which are commercially available, e.g., the OPADRY seriesfrom Colorcon. See, U.S. Pat. No. 4,543,370, the disclosure of which isincorporated by reference.

Suitably, the coated drug-ion exchange resin complexes of the inventionare still within the size range identified above. The coated drug-ionexchange resin composition may be stored for future use, packaged, orpromptly formulated with conventional pharmaceutically acceptablecarriers to prepare finished ingestible compositions for deliveryorally, nasogastric tube, or via other means. The compositions accordingto this invention may, for example, take the form of solid preparationssuch as capsules (which may include liquigels or the granular hybridcoated ion exchange resin complexes), powders, tablets, caplets, etc.

Finished Formulations

The hybrid coated drug-ion exchange resin complexes of the presentinvention, can readily be formulated with pharmaceutically acceptableexcipients according to methods well known to those of skill in the art.In one embodiment, these formulations contain a coated opioid drug-ionexchange resin complex of the invention, optionally with a releaseretardant. In another embodiment, such formulations may also contain aselected amount of uncoated drug-ion exchange resin complex, optionallywith a release retardant as described herein.

In yet another embodiment, the formulations of the invention may containmore than one active component. For example, the formulation may containmore than one drug loaded into an ion exchange resin to form a complexof the invention.

The coated drug-ion exchange resin complex of the invention may beformulated for delivery by any suitable route. However, the complex isparticularly well suited for oral delivery and is so formulated.

In one particularly desirable embodiment, the coated drug-ion exchangeresin complex of the invention is formulated into a solid oral dose formsuch as a modified release tablet or granules in a capsule. In oneembodiment, the solid dosage form contains at least one hybrid coatedopioid-ion exchange resin complex of the invention in admixture withcomponents such as fillers, lubricants, and disintegrants. In oneembodiment, one or more fillers is present in an amount of about 1 to70% w/w of the dosage unit. For example, a dosage unit may contain about5 to 15% w/w calcium silicate, about 10 to 50% w/w microcrystallinecellulose, about 10 to about 50% w/w lactose, or combinations of thesefillers/diluents. In another embodiment, one or more lubricants may bepresent in an amount of about 0.01% to about 5% w/w of the dosage unit.For example, a dosage unit may contain about 0.2 to about 2% w/wamorphous silica, about 0.5 to about 5% w/w talc, about 0.05 to about1.5% magnesium stearate, or combinations of these lubricants. In oneembodiment, the solid dosage unit contains about 1 to about 20% w/w of adisintegrant. For example, about 4 to about 8% w/w crospovidone may bepresent in the solid dosage unit alone or in combination with anotherdisintegrant.

The drug-ion exchange resin coated compositions may be formulated usingconventional pharmaceutically acceptable carriers or excipients and wellestablished techniques. Without being limited thereto, such conventionalcarriers or excipients include diluents (e.g., microcrystallinecellulose, lactose), fillers (e.g., calcium silicate), binders andadhesives (i.e., cellulose derivatives and acrylic derivatives),lubricants (i.e., magnesium or calcium stearate, or vegetable oils,polyethylene glycols, talc, sodium lauryl sulfate, amorphous silica,polyoxy ethylene monostearate), thickeners, solubilizers, humectants,disintegrants (e.g., crospovidone), colorants, flavorings, stabilizingagents, sweeteners, and miscellaneous materials such as buffers andadsorbents in order to prepare a particular pharmaceutical composition.The stabilizing agents may include preservatives and anti-oxidants,amongst other components which will be readily apparent to one ofordinary skill in the art.

When formulated into a liquid suspension, a variety of these oradditional excipients may be included. For example, a suspension maycontain thickeners or humectants. Suitable thickeners include, e.g.,tragacanth; xanthan gum; bentonite; starch; acacia and lower alkylethers of cellulose (including the hydroxy and carboxy derivatives ofthe cellulose ethers). Examples of cellulose include, e.g.,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, microcrystalline cellulose (MCC), and MCC with sodiumcarboxylmethyl cellulose. In one embodiment, tragacanth is used andincorporated in an amount of from about 0.1 to about 1.0% weight pervolume (w/v) of the composition, and more preferably about 0.5% w/v ofthe composition. Xanthan gum is used in the amount of from about 0.025to about 0.5% w/v and preferably about 0.25% w/v. A humectant may beincluded to give the suspension greater viscosity and stability.Suitable humectants useful in the finished formulations includeglycerin, polyethylene glycol, propylene glycol and mixtures thereof.

Oral liquid suspensions of the present invention may also comprise oneor more surfactants in amounts of up to about 5.0% w/v and preferablyfrom about 0.02 to about 3.0% w/v of the total formulation. Thesurfactants useful in the preparation of the finished compositions ofthe present invention are generally organic materials which aid in thestabilization and dispersion of the ingredients in aqueous systems for asuitable homogenous composition. Preferably, the surfactants of choiceare non-ionic surfactants such as poly(oxyethylene) (20) sorbitanmonooleate and sorbitan monooleate. These are commercially known asTWEENS and SPANS and are produced in a wide variety of structures andmolecular weights.

Whereas any one of a number of surfactants may be used, preferably acompound from the group comprising polysorbate copolymers(sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethanediyl)) is employed.This compound is also added functions to keep any flavors and sweetenershomogeneously dissolved and dispersed in solution.

Suitable polysorbates include polysorbate 20, polysorbate 40,polysorbate 80 and mixtures thereof. Most preferably, polysorbate 80 isemployed. The surfactant component will comprise from about 0.01 toabout 2.0% w/v of the total composition and preferably will compriseabout 0.1% w/v of the total weight of the composition.

A second emulsifer/surfactant useful in combination with polysorbatesmay be employed and is preferably a poloxamer such as Poloxamer 407.Poloxamer 407 has an HLB (hydrophilic/lipophilic balance) of about 22and is sold under the tradename Pluoronic-127 (BASF-NJ). The twosurfactants can be employed in substantially equivalent amounts. Forexample, the Poloxamer 407 and polysorbate 80 may each be employedtogether at levels of approximately from about 0.02 to about 4.0% w/v ofthe total weight of the formulation.

Aqueous suspensions may be obtained by dispersing the drug-ion exchangeresin compositions in a suitable aqueous vehicle, optionally with theaddition of suitable viscosity enhancing agent(s) (e.g., cellulosederivatives, xanthan gum, etc). Non-aqueous suspensions may be obtainedby dispersing the foregoing compositions in a suitable non-aqueous basedvehicle, optionally with the addition of suitable viscosity enhancingagent(s) (e.g., hydrogenated edible fats, aluminum state, etc.).Suitable non-aqueous vehicles include, for example, almond oil, arachisoil, soybean oil or soybean oil or fractionated vegetable oils such asfractionated coconut oil.

Useful preservatives include, but are not limited to, sodium benzoate,benzoic acid, potassium sorbate, salts of edetate (also known as saltsof ethylenediaminetetraacetic acid, or EDTA, such as disodium EDTA),parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, etc.),and sorbic acid. Amongst useful preservatives include chelating agentssome of which are listed above and other chelating agents, e.g.,nitrilotriacetic acid (NTA); ethylenediaminetetracetic acid (EDTA),hydroxyethylethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DPTA), 1,2-Diaminopropanetetraaceticacid (1,2-PDTA); 1,3-Diaminopropanetetraacetic acid (1,3-PDTA);2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA);1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA);ethylenediamine (EDAMINE);Trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CDTA);ethylenediamine-N,N′-diacetate (EDDA); phenazine methosulphate (PMS);2,6-Dichloro-indophenol (DCPIP); Bis(carboxymethyl)diaza-18-crown-6(CROWN); porphine; chlorophyll; dimercaprol (2,3-Dimercapto-1-propanol);citric acid; tartaric acid; fumaric acid; malic acid; and salts thereof.The preservatives listed above are exemplary, but each preservative mustbe evaluated in each formulation, to assure the compatibility andefficacy of the preservative. Methods for evaluating the efficacy ofpreservatives in pharmaceutical formulations are known to those skilledin the art. Preferred preservatives are the paraben preservativesincluding, methyl, ethyl, propyl, and butyl paraben. Methyl and propylparaben are most preferable. Preferably, both methyl and propyl parabenare present in the formulation in a ratio of methyl paraben to propylparaben of from about 2.5:1 to about 16:1, preferably 9:1.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist: Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, high fructose corn syrup, dextrose,sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrupsolids and sugar alcohols such as sorbitol, xylitol, mannitol andmixtures thereof.

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular liquid suspension. This amount willnormally be 0.001 to about 90% by weight, per volume of the final liquidsuspension composition, when using an easily extractable sweetener. Thewater-soluble sweeteners described above, are preferably used in amountsof about 5 to about 70% by weight per volume, and most preferably fromabout 10 to about 50% by weight per volume of the final liquidsuspension composition. In contrast, the artificial sweeteners [e.g.,sucralose, acesulfame K, and dipeptide based sweeteners] are used inamounts of about 0.005 to about 5.0% and most preferably about 0.01 toabout 2.5% by weight per volume of the final liquid suspensioncomposition. These amounts are ordinarily necessary to achieve a desiredlevel of sweetness independent from the flavor level achieved fromflavor oils.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, menthol, artificial vanilla, cinnamon, variousfruit flavors, both individual and mixed, essential oils (i.e., thymol,eucolyptol, menthol and methyl salicylate) and the like arecontemplated. The amount of flavoring employed is normally a matter ofpreference subject to such factors as flavor type, individual flavor,and strength desired. Thus, the amount may be varied in order to obtainthe result desired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. The flavorings are generally utilized in amounts thatwill vary depending upon the individual flavor, and may, for example,range in amounts of about 0.01 to about 3% by weight per volume of thefinal composition weight.

The colorants useful in the present invention include the pigments suchas titanium dioxide that may be incorporated in amounts of up to about1% by weight per volume, and preferably up to about 0.6% by weight pervolume. Also, the colorants may include dyes suitable for food, drug andcosmetic applications, and known as D&C and F.D. & C. dyes and the like.The materials acceptable for the foregoing spectrum of use arepreferably water-soluble. Illustrative examples include indigoid dye,known as F.D. & C. Blue No. 2, which is the disodium salt of5,5-indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1 comprises a triphenylmethane dye and is the monosodium saltof 4-[4-N-ethylp-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].A full recitation of all F.D. & C. and D. & C. and their correspondingchemical structures may be found in the Kirk-Othmer Encyclopedia ofChemical Technology, in Volume 5, at Pages 857-884, which text isaccordingly incorporated herein by reference. Optionally, these orsimilar components may also be included in a non-functional coating fora tablet.

Suitable oils and fats that are usable would include partiallyhydrogenated vegetable or animal fats, such as coconut oil, palm kerneloil, beef tallow, lard, and the like. These ingredients are generallyutilized in amounts with respect to the ingestible product of up toabout 7.0% by weight, and preferably up to about 3.5% by weight of thefinal product.

Wetting agents also may be employed in the inventive compositions tofacilitate the dispersion of any hydrophobic ingredients. Theconcentration of wetting agents in the composition should be selected toachieve optimum dispersion of the ingredient within the composition withthe lowest feasible concentration of wetting agent. It should beappreciated that an excess concentration of wetting agent may cause thecomposition, as a suspension, to flocculate. Those skilled in the artare well versed in suitable empirical methods to determine theappropriate wetting agents and concentrations to achieve optimumdispersion and avoid flocculation. Suitable wetting agents are listed inthe US Pharmacoepia 29.

Where desired, the hybrid coated drug-ion exchange granules or particlesof the invention are loaded into a capsule. Typically, a capsule is ashell which readily dissolves in the stomach and can be made from avariety of orally ingestible products (e.g., gelatin,hydroxypropylmethylcellulose (vegetarian)). Thus, the capsule does notaffect the release profile of the composition of the invention. Suitablecapsule shells are readily obtained from a variety of commercial sourcesincluding, e.g., Capsuline, CapsuleGel, Shinogi, and United Capsules).Typically, the capsule shell selected is of size 0 or 1. The amount ofgranules loaded into the capsule depends upon the size of the capsuleand the amount of active desired. For example, where the drug isdesigned to provide the equivalent of 100 mg of morphine sulfate, 450 mgof hybrid coated morphine-cation exchange resin may be loaded into asize 0 capsule. However, other suitable shell sizes can be readilydetermined.

Optionally, where needed to facilitate flow while filling a capsule, acoated drug-ion exchange resin complex may be mixed with a lubricant.Suitable lubricants can be readily selected from among those known inthe art, e.g., magnesium stearate, talc, etc.

The following examples are provided to more specifically illustrate themodified release compositions of the present invention and not intendedto be limiting. They are for illustrative purposes only and it isrealized that changes and variations can be made without departing fromthe spirit and scope of the invention.

Example 1 Preparation of Hybrid Coated Morphine Resin Complex

The following example describes the preparation of a hybrid coatedmorphine-ion exchange resin complex, in which the cation exchange resinutilized is the Amberlite IRP-69 brand cross-linked polysytrene resin.The formed morphine-ion exchange resin complex may be referred to asmorphine polistyrex for convenience.

Ingredient Quantity Morphine Resin Complex Morphine Sulfate 810 gPurified Water 13600 g AMBERLITE IRP-69 RESIN 1358 g KOLLIDON K-30polyvinylpyrrolidone 180 g Purified water 421 g Coated Morphine ResinComplex KOLLICOAT SR-30D polymer system 693.38 g (30% dispersion)(208.0164 g solids) Triacetin 10.37 g SURETERIC 90G18507 White 41.6 gpolyvinylacetate phthalate polymer system Purified Water 554.65 gMorphine Resin Complex 600 g

The following was performed at room temperature unless otherwisespecified. The morphine resin complex was prepared by first dissolving810 g of morphine sulfate in 13.6 liters of purified water, and thenslowly adding 1358 g of AMBERLITE™ IRP-69 resin with continuous mixingusing a propeller mixer (ARROW™). The dispersion was mixed for 1 hourand upon completion, the dispersion was filtered through a Buchnerfunnel with the aid of vacuum. The dispersion/filtration process wasrepeated twice with 4800 g of purified water. The wet resin complex wasthen dried in a VECTOR™ FLM-1 fluid bed processor at 50° C. until themoisture content was about 15-25%. In a separate container 180 g ofKOLLIDON K-30™ polyvinylpyrrolidone (PVP) was added into 421 g ofpurified water and mixed using a propeller mixer (ARROW™) untildissolved. The aqueous KOLLIDON K-30™ PVP solution was then slowly addedto the wet resin complex in a Hobart type mixer (Kitchen Aid) to form auniform mass. The wet mass was again dried at 50° C. in a VECTOR™ FLM-1fluid bed processor to a moisture content of about 15-25%, therebyforming granules. The semi-dried granules were then milled through a 40mesh screen using CO-MIL™ brand mill and drying continued under 50° C.until the moisture content was between 3-7%. The dried granules werethen milled through a 40 mesh screen using CO-MIL™ brand mill [QUADRO].The 40 mesh screen allows particles of less than 420 microns to passthrough.

In a separate container, 10.37 g of triacetin and 693.38 g of KOLLICOAT™SR-30D (which is a 30% dispersion of a polyinyl acetate polymer systemas described above) were mixed for 1 hour (solution-A). 41.6 g ofSURETERIC™ 90G18507 White polyinylacetate phthalate (PVAP) was dispersedin 554.65 g of purified water and mixed for 30 minutes (solution-B)using a propeller mixer (ARROW™). Solution-B was added into Solution-Aand mixed for 1 hour using a propeller mixer (ARROW™). The final coatingsolution was passed through a 40 mesh screen. The coating process wasperformed in a VECTOR™ FLM-1 fluid bed processor by applying 1,200 g ofcoating solution to 600 g of Morphine Resin Complex using the WURSTERprocess that resulted in 40% weight gain. The coating conditions werecontrolled at a product temperature of 25-35° C., air flow of 10-25 cfm,nozzle pressure of 2-3 kg/cm², accelerator air pressure of 1 kg/cm², andspray rate of 2.5-10 g/min so that uniform coating was achieved. Thecoated Morphine Resin Complex was then placed at 60° C. in a VWR™convection oven for 5 hours.

The resulting hybrid coated morphine resin complex still passes througha 40 mesh screen.

The dried hybrid coated morphine resin complex is ready for tabletting(Example 2), formulation into a suspension (Example 3) or assembly intoa capsule (Example 4).

Example 2 Tabletting of Hybrid Coated Morphine-Resin Complex

Ingredient Quantity Hybrid coated Morphine Ion Resin Complex 266.84 g(from example 1) Calcium silicate, (RXCIPIENT ™ FM1000) 40.5 g Silicondioxide, (RXCIPIENT ™ GL100) 4.5 g Microcrystalline cellulose, (AVICEL ®PH 101) 127.74 g Crospovidone, (KOLLIDON ™ CL-SF) 18 g Lactosemonohydrate, (FLOWLAC ™ 100) 96.6 g Talc (IMPERIAL ™ 500) 9 g MagnesiumStearate 2.1 g TOTAL 565.28 g Hybrid Coated Morphine Modified Releasetablets OPADRY ® WHITE YS-1-18202-A-PVAP 20 g Purified water 80 g HybridCoated Morphine ER tablets 200 g

Hybrid coated Morphine Ion Resin Complex (266.84 g, from example 1),calcium silicate (RXCIPIENT™ FM1000) (40.5 g), silicon dioxide(RXCIPIENT™ GL100) (4.5 g), microcrystalline cellulose (AVICEL® PH 101)(127.74 g), crospovidone (KOLLIDON™ CL-SF) (18 g), lactose monohydrate(FLOWLAC™ 100) (96.6 g), and talc (IMPERIAL™ 500) (9 g) were passedthrough 40 mesh screen and mixed for 10 minutes using a cube blender(ERWEKA™ AR-402). Magnesium stearate (2.1 g) was passed through 40 meshscreen and added into the blender and further mixed for 5 minutes. Theblend was compressed into tablets using a rotary tablet press (MINIPRESS™) fitted with a 0.3440″×0.7500″ capsule shape tooling. Tabletswere compressed with weight of 942.14 mg (equivalent to 100 mg morphinesulfate), hardness of 7-11 kp, at machine speed of 5-30 rpm, resultingin tablets of approximately 1 gram each in size.

In order to provide a desired, non-functional coating on the tablets,OPADRY®WHITE YS-1-18202-A (20 g) was dispersed into 80 g purified waterand mixed for 45 minutes using a propeller mixer (ARROW™). The coatingprocess was performed in a perforated coating pan (VECTOR™ LDCS-5) byapplying 20 g of coating solution to 200 of the approximately 1 gMorphine-Ion Exchange Modified Release tablets to provide about a 2% wtgain to each tablet. The coating conditions were controlled using anexhaust temperature of 30° C. and a spray rate of 5 g/min.

This tabletted form of the hybrid coated morphine-cation exchange resincomplex exemplified in Example 2 was designed to have desired abuseresistance and an in vivo release profile essentially the same as thecurrently commercially available Kadian® 100 mg morphine sulfate capsulewhich has a 12-24 hours extended release formulation.

In vitro dissolution was assessed in the USP Standard paddle test(apparatus 2), at a speed of 50 rpm, a bath temperature of 37±0.5° C.,in a dissolution medium of 500 mL 0.1 N hydrochloric acid for 1 hour,followed by addition of 500 mL of phosphate buffer to a pH 7.5. Thetabletted form of the hybrid coated morphine-cation exchange resincomplex has an in vitro dissolution release rate of morphine of 11.4% in1 hour, 49.4% in 2 hours, 67.4% in 3 hours, 77.0% in 4 hours, and 95.1%in 12 hours. It will be understood by one of skill in the art that twocompositions can have different in vitro dissolution rates, yet providebioequivalent in vivo release rates.

Example 3 Preparation of Hybrid Coated Morphine Modified ReleaseSuspension

Ingredient Quantity Placebo Suspension Base Citric acid, anhydrous 8 gHigh Fructose Corn Syrup 42 1,200 g Sucrose 600 g Starch 92 g Xanthangum 7.6 g Glycerin 400 g Methylparaben 7.2 g Propylparaben 0.8 gStrawberry Banana Flavor 44.88 g Purified Water QS 3484.91 g HybridCoated Morphine - Ion Exchange Resin Complex Modified Release SuspensionPurified Water 200 g Sodium Metabisulfite 1 g Polysorbate 80 1 g HybridCoated Morphine Ion Exchange Resin 18.59 g (From Example 1) PlaceboSuspension Base 871.2 g Purified Water QS 1,000 mL

A placebo suspension base was prepared by first dissolving 8 g of citricacid in an appropriate amount of purified water, followed by adding 600g of sucrose and 1200 g of high fructose corn syrup to achieve completesolution. 92 g of starch was then slowly introduced to the maincontainer under high shear mixing condition to achieve uniformdispersion. In another container, 400 g glycerin was added and heated to45-50° C. followed by addition of 7.2 g of methylparaben and 0.8 gpropylparaben. After both of the parabens were completely dissolved, thesolution was cooled to room temperature and 7.6 g Xanthan gum was slowlyintroduced to the solution to form a uniform dispersion. The gumdispersion was then transferred to the main container under highspeed/shear mixing condition to achieve uniform suspension. 44.88 g ofStrawberry/Banana flavor was added and the Placebo suspension base wasachieved by addition of the remaining purified water and mixed untiluniform.

To prepare the suspension, 200 g water was weighed to the main containerfollowed by the addition of 1 g of Sodium Metabisulfite and Polysorbate80. These components were mixed until completely dissolved. 871.2 g ofPlacebo Suspension Base was then added. The hybrid coated morphine ionexchange complex of example 1 was then added slowly under conditions ofgentle mixing. The final suspension was obtained by adding anappropriate amount of purified water to make up the volume to 1000 mLfollowed by gentle mixing until a uniform suspension is obtained.

Example 4 Hybrid Coated Morphine Modified Release Granules in Capsule

Ingredient Quantity Coated Morphine Ion Exchange Resin Complex 450 g(From Example 1) Magnesium Stearate  4.5 g

A hybrid coated morphine-ion exchange resin complex that may be preparedaccording to example 1 is taken and blended with 1% Magnesium Stearatein a cube blender for 3 minutes at batch scale.

Approximately 454 mg of the blend is then filled into a Size 0 hardgelatin capsule to provide an amount of active equivalent to 100 mgmorphine sulfate.

Example 5 Preparation of Hybrid Coated Morphine-Resin Complex

This example illustrates the preparation of a hybrid coated opioid-ionexchange resin complex with a different hybrid coating than thatillustrated in Example 1. This hybrid coating contains a higherpercentage of the barrier coating polymer as compared to the entericpolymer.

Ingredient Quantity Morphine Resin Complex Morphine Sulfate 810 gPurified Water 13600 g AMBERLITE IRP-69 RESIN 1358 g KOLLIDON K-30 ™(PVP) 180 g Purified water 421 g Hybrid coated Morphine Resin ComplexKOLLICOAT SR-30D ™ polymer system 770.42 g (30% dispersion) (231.126 gsolids) Triacetin 11.53 g SURETERIC ™ 90G18507 White brand 17.34 g(PVAP) Purified Water 500.71 g Morphine Resin Complex 600 g

The morphine ion exchange resin complex was prepared by first dissolving810 g of morphine sulfate in 13.6 liters of purified water, and thenslowly adding 1358 g of AMBERLITE™ IRP-69 resin with continuous mixingusing a propeller mixer (ARROW™). The dispersion was mixed for 1 hourand upon completion, the dispersion was filtered through a Buchnerfunnel with the aid of vacuum. The dispersion/filtration process wasrepeated twice with 4800 g of purified water. The wet resin complex wasthen dried in a VECTOR™ FLM-1 fluid bed processor at 50° C. untilmoisture content was about 15-25%. In separate container 180 g ofKOLLIDON™ K-30 PVP was added into 421 g of purified water and mixedusing propeller mixer (ARROW™) until dissolved. The aqueous KOLLIDON™K-30 solution was then slowly added to the wet resin complex in a Hobarttype mixer (Kitchen Aid) to form a uniform mass. The wet mass was againdried at 50° C. in a VECTOR™ FLM-1 fluid bed processor to the moisturecontent about 15-25%. The semi-dried granules were then milled through a40 mesh screen using CO-MIL™ brand mill and continued drying under 50°C. until the moisture content was between 3-7%. The dried granules werethen milled through a 40 mesh screen using CO-MIL™ brand mill [QUADRO].

In separate container, 11.53 g of triacetin and 770.42 g of KOLLICOAT™SR-30D polymer system were mixed for 1 hour (solution-A). 17.34 g ofSURETERIC™ 90G18507 white PVAP was dispersed in 500.71 g of purifiedwater and mixed for 30 minutes (solution-B) using propeller mixer(ARROW™). Solution-B was added into Solution-A and mixed for 1 hourusing propeller mixer (ARROW™). The final coating solution was passedthrough 40 mesh screen. The coating process was performed in a VECTOR™FLM-1 fluid bed processor by applying 1,200 g of hybrid coating solutionto 600 g of Morphine Ion Resin Complex of this example using the WURSTERprocess that resulted in 40% weight gain. The coating conditions werecontrolled at a product temperature of 25-35° C., air flow of 10-25 cfm,nozzle pressure of 2-3 kg/cm2, accelerator air pressure of 1 kg/cm2, andspray rate of 2.5-10 g/min so that uniform coating was achieved. Thecoated Morphine Resin Complex was then placed at 60° C. in a VWR™convection oven for 5 hours.

Example 6 Preparation of Hybrid Coated Morphine Resin Complex

This example illustrates the preparation of a coated opioid-ion exchangeresin complex with a different hybrid coating than that illustrated inExample 1 (or Example 5). This hybrid coating contains a higherpercentage by weight of the enteric coating polymer as compared to thepercentage of this component in Example 1 (and Example 5).

Ingredient Quantity Morphine Ion Exchange Resin Complex Morphine Sulfate810 g Purified Water 13600 g AMBERLITE IRP-69 Resin 1358 g KOLLIDON K-30PVP 180 g Purified water 421 g Coated Morphine Ion Resin ComplexKOLLICOAT SR-30D polymer system 641.979 g (192.5937 g solids) (30%dispersion) Triacetin 9.633 g SURETERIC 90G18507 White 57.785 g PVAPsystem Purified Water 590.603 g Morphine Resin Complex 600 g

The morphine resin complex was prepared by first dissolving 810 g ofmorphine sulfate in 13.6 liters of purified water, and then slowlyadding 1358 g of AMBERLITE™ IRP-69 resin with continuous mixing usingpropeller mixer (ARROW™). The dispersion was mixed for 1 hour and uponcompletion, the dispersion was filtered through a filtration apparatus(Buchner funnel) with the aid of vacuum. The dispersion/filtrationprocess was repeated twice with 4800 g of purified water. The wet resincomplex was then dried in a VECTOR™ FLM-1 fluid bed processor at 50° C.until moisture content was about 15-25%. In separate container 180 g ofKOLLIDON™ K-30 PVP was added into 421 g of purified water and mixedusing propeller mixer (ARROW™) until dissolved. The KOLLIDON™ K-30 PVPsolution was then slowly added to the wet resin complex in a Hobart typemixer (Kitchen Aid) to form uniform mass. The wet mass was again driedat 50° C. in a VECTOR™ FLM-1 fluid bed processor to the moisture contentaround 15-25%. The semi-dried granules were then milled through a 40mesh screen using CO-MIL™ brand mill and continued drying under 50° C.until the moisture content was between 3-7%. The dried granules werethen milled through a 40 mesh screen using CO-MIL™ brand mill [QUADRO].

In a separate container, 9.633 g of triacetin and 641.979 g ofKOLLICOAT™ SR-30D polyvinylacetate polymer system were mixed for 1 hour(solution-A). 57.785 g of SURETERIC™ 90G18507 white PVAP was dispersedin 590.603 g of purified water and mixed for 30 minutes (solution-B)using a propeller stirrer (ARROW™) Solution-B was added into Solution-Aand mixed for 1 hour using a propeller stirrer (ARROW™). The finalcoating solution was passed through 40 mesh screen. The coating processwas performed in a VECTOR™ FLM-1 fluid bed processor by applying 1,200 gof coating solution to 600 g of Morphine Resin Complex using WURSTERprocess that resulted in 40% weight gain. The coating conditions werecontrolled at an product temperature of 25-35° C., air flow of 10-25cfm, nozzle pressure of 2-3 kg/cm², accelerator air pressure of 1kg/cm², and spray rate of 2.5-10 g/min so that uniform coating wasachieved. The coated Morphine Resin Complex was then placed at 60° C. inVWR™ convection oven for 5 hours.

Example 7 Preparation of Hybrid Coated Morphine Resin Complex

Ingredient Quantity Morphine Resin Complex Morphine Sulfate 450 gPurified Water 5 L AMBERLITE IRP-69 Resin 807 g KOLLICOAT SR-30D polymer501 g system Coated Morphine Resin Complex KOLLICOAT SR-30D polymer693.38 g system (30% dispersion) Triacetin 10.37 g SURETERIC 90G 18507White 41.6 g PVAP system Purified Water 554.65 g Morphine Resin Complex600 g

The morphine resin complex is prepared by first dissolving 450 g ofmorphine sulfate in 5 liters of purified water, and then slowly adding807 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersionis mixed for 1 hour and upon completion, the dispersion is filteredthrough a filtration apparatus such as a Buchner funnel with the aid ofvacuum. The dispersion/filtration process is repeated twice with 4800 gof purified water. The wet resin complex is then dried in a VECTOR™FLM-1 fluid bed processor at 50° C. until moisture content is about15-25%. KOLLICOAT™ SR-30D of 501 g is then slowly added to the wet resincomplex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. Thewet mass is again dried at 50° C. in a VECTOR™ FLM-1 fluid bed processorto the moisture content around 20%. The semi dried granules are thenmilled through a 40 mesh screen using CO-MIL™ brand mill and dryingcontinued at 50° C. until the moisture content is about 3-7%. The driedgranules are then milled through a 40 mesh screen using CO-MIL™ brandmill [QUADRO].

In a separate container, 10.37 g of triacetin and 693.38 g of KOLLICOAT™SR-30D PVA polymer system are mixed for 1 hour (solution-A). SURETERIC™90G 18507 White PVAP is dispersed in 554.65 g of purified water andmixed for 30 minutes (solution-B) using propeller mixer (ARROW™).Solution B is added into Solution A and mixed for 1 hour using propellermixer (ARROW™). The final coating is passed through 40 mesh screen. Thecoating process is performed in a VECTOR™ FLM-1 fluid bed processor byapplying 1,200 g of coating solution to 600 g of Morphine Resin Complexusing the WURSTER process that resulted in 40% weight gain. The coatingconditions are controlled at an inlet temperature of 25-35° C., air flowof 10-25 cfm, nozzle pressure of 2-3 kg/cm², accelerator air pressure of1 kg/cm², and spray rate of 2.5-10 g/min so that uniform coating isachieved. The coated Morphine Resin complex is then placed at 60° C. inVWR™ convection oven for 5 hours.

The dried coated morphine resin complex is ready for formulation, e.g.,as described in Example 8.

Example 8 Preparation of Morphine Modified Release Tablets

Ingredient Quantity Hybrid coated Morphine Resin Complex (from example7) 266.84 g Calcium silicate (RXCIPIENT ™ FM 1000) 40.5 g Silicondioxide (RXCIPIENT ™ GL 100) 4.5 g Microcrystalline cellulose (AVICEL ®PH 101) 127.74 g Crospovidone (KOLLIDON ™ CL-SF) 18 g Lactosemonohydrate (FLOWLAC ™ 100) 96.6 g Talc (IMPERIAL ™ 500) 9 g MagnesiumStearate 2.1 g TOTAL (uncoated tablet) 565.28 g Hybrid Coated MorphineModified Release Tablets OPADRY ® WHITE YS-1-18202-A 20 g Purified water80 g Morphine Modified Release Tablets (containing coated 200 g morphineresin complex)

Hybrid coated Morphine Resin Complex (from example 7) (266.84 g),calcium silicate (RXCIPIENT™ FM 1000) (40.5 g), silicon dioxide(RXCIPIENT™ GL 100) (4.5 g), microcrystalline cellulose (AVICEL® PH 101)(127.74 g), crospovidone (KOLLIDON™ CL-SF) (18 g), lactose monohydrate(FLOWLAC™ 100) (96.6 g), and talc (IMPERIAL™ 500) (9 g) are passedthrough 40 mesh screen and mixed for 10 minutes using a cube blender(ERWEKA™ AR-402). Magnesium stearate (2.1 g) is passed through 40 meshscreen and added into blender and further mixed for 5 minutes. The blendis compressed into tablets using a rotary tablet press (MINIPRESS™)fitted with a 0.3440×0.7500 capsule shape tooling. Tablets arecompressed with weight of 942.14 mg (equivalent to 100 mg morphinesulfate), hardness of 7-11 kp, at machine speed of 5-30 rpm.

A non-functional coating may be prepared and applied as follows. OPADRY®WHITE YS-1-18202-A brand (20 g) is dispersed into 80 g purified waterand mixed for 45 minutes using propeller mixer (ARROW™). The coatingprocess is performed in a perforated coating pan (VECTOR™ LDCS-5) byapplying 20 g of coating solution to 200-1 g Morphine ER tablets. Thecoating conditions are controlled by exhaust temperature of 30° C. andspray rate of 5 g/min.

Example 9 Preparation of Hybrid Coated Oxycodone Ion Exchange ResinComplex

Ingredient Quantity Oxycodone Resin Complex Oxycodone HCl 450 g PurifiedWater 5 L AMBERLITE IRP-69 Resin 1,427 g KOLLICOAT SR-30D polymer 500 gsystem (30% dispersion) Coated Oxycodone Resin Complex KOLLICOAT SR-30Dpolymer 693.38 g system (30% dispersion) Triacetin 10.37 g SURETERIC 90G18507 White 41.6 g PVAP system Purified Water 554.65 g Oxycodone IonExchange Resin 600 g Complex

An Oxycodone ion exchange resin complex may be prepared in accordancewith the present invention as follows. 450 g of oxycodone HCl isdissolved in 5 liters of purified water, and then slowly adding 807 g ofAMBERLITE™ IRP-69 resin with continuous mixing. The dispersion is mixedfor 1 hour and upon completion, filter the dispersion through afiltration apparatus (Buchner funnel) with the aid of vacuum. Thedispersion/filtration process is repeated twice with 4800 g of purifiedwater. The wet resin complex is then dried in a VECTOR™ FLM-1 fluid bedprocessor at 50° C. until moisture content is about 15-25%. KOLLICOAT™SR-30D of 501 g is then slowly added to the wet resin complex in aHobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass isagain dried at 50° C. in a VECTOR™ FLM-1 fluid bed processor to themoisture content around 20%. The semi dried granules are then milledthrough a 40 mesh screen using CO-MIL™ brand mill and continued dryingat 50° C. until moisture content is about 3-7%. The dried granules arethen milled through a 40 mesh screen using CO-MIL™ brand mill [QUADRO].

In a separate container, 10.37 g of triacetin and 693.38 g of KOLLICOAT™SR-30D are mixed for 1 hour (solution-A). SURETERIC™ 90G 18507 White isdispersed in 554.65 g of purified water and mixed for 30 minutes(solution-B) using propeller mixer (ARROW™). Solution B is added intoSolution A and mixed for 1 hour using propeller mixer (ARROW™). Thefinal coating is passed through 40 mesh screen. The coating process isperformed in a VECTOR™ FLM-1 fluid bed processor by applying 1,200 g ofcoating solution to 600 g of Oxycodone Resin Complex using WURSTERprocess that results in 40% weight gain. The coating conditions arecontrolled at an inlet temperature of 25-35° C., air flow of 10-25 cfm,nozzle pressure of 2-3 kg/cm², accelerator air pressure of 1 kg/cm², andspray rate of 2.5-10 g/min so that uniform coating is achieved. Thecoated oxycodone complex is then placed at 60° C. in VWR™ convectionoven for 5 hours.

Example 10 Preparation of Hybrid Coated Oxycodone Modified ReleaseTablets

Ingredient Quantity Hybrid Coated Oxycodone Resin Complex 266.84 g (fromexample 9) Calcium silicate (RXCIPIENT ™ FM 1000) 40.5 g Silicon dioxide(RXCIPIENT ™ GL 100) 4.5 g Microcrystalline cellulose (AVICEL ® PH 101)127.74 g Crospovidone (KOLLIDON ™ CL-SF) 18 g Lactose monohydrate(FLOWLAC ™ 100) 96.6 g Talc (IMPERIAL ™ 500) 9 g Magnesium Stearate 2.1g TOTAL 565.28 g Coated Oxycodone Modified Release Tablets OPADRY ®WHITE YS-1-18202-A 20 g Purified water 80 g Uncoated Oxycodone ERTablets 200 g

Using a coated Oxycodone Resin Complex (that may be prepared as inExample 9) (266.84 g), calcium silicate (RXCIPIENT™ FM 1000) (40.5 g),silicon dioxide (RXCIPIENT™ GL 100) (4.5 g), microcrystalline cellulose(AVICEL® PH 101) (127.74 g), crospovidone (KOLLIDON™ CL-SF) (18 g),lactose monohydrate (FLOWLAC™ 100) (96.6 g), and talc (IMPERIAL™ 500) (9g) are passed through 40 mesh screen and mixed for 10 minutes using cubeblender (ERWEKA™ AR-402). Magnesium stearate (2.1 g) is passed through a40 mesh screen, added into the blender and further mixed for 5 minutes.The blend is compressed into tablets using rotary tablet press(MINIPRESS™) fitted with a 0.3440×0.7500 capsule shape tooling. Tabletsare compressed with weight of 942.14 mg (equivalent to 100 mg morphinesulfate), hardness of 7-11 kp, at machine speed of 5-30 rpm.

A non-functional coating may be prepared and applied as follows.OPADRY®WHITE YS-1-18202-A-20 g is dispersed into purified water (80 g)and mixed for 45 minutes using propeller mixer (ARROW™). The coatingprocess is performed in a perforated coating pan (VECTOR™ LDCS-5) byapplying 20 g of coating solution to 200-1 g Oxycodone modified releasetablets. The coating conditions are controlled by exhaust temperature of30° C. and spray rate of 5 g/min.

Example 11 Preparation of Hybrid Coated Opioid Resin Complex Using DowexResin

A coated morphine ion exchange resin complex may be prepared asdescribed in Example 1, using a strongly acidic Dow™ resin in place ofthe Amberlite™ resin described in Example 1.

Ingredient Quantity Morphine Ion Resin Complex Morphine Sulfate 450 gPurified Water 5 L DOW XYS-40010.00 807 g KOLLICOAT SR-30D polymer 501 gsystem (30% dispersion) Hybrid Coated Morphine Ion Resin ComplexKOLLICOAT SR-30D polymer 693.38 g system (30% dispersion) Triacetin10.37 g SURETERIC 90G 18507 White 41.6 g PVAP system Purified Water554.65 g Morphine Ion Resin Complex 600 g

A morphine sulfate complex may be prepared by first dissolving 450 g ofmorphine sulfate in 5 liters of purified water, and then slowly adding807 g of DOWEX™ resin with continuous mixing. The dispersion is mixedfor 1 hour and upon completion, the dispersion is filtered through afiltration apparatus (Buchner funnel) with the aid of vacuum. Thedispersion/filtration process is repeated twice with 4800 g of purifiedwater. The wet resin complex is then dried in a VECTOR™ FLM-1 fluid bedprocessor at 50° C. until moisture content is about 15-25%. KOLLICOAT™SR-30D of 501 g is then slowly added to the wet resin complex in aHobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass isagain dried at 50° C. in a VECTOR™ FLM-1 fluid bed processor to themoisture content around 20%. The semi dried granules are then milledthrough a 40 mesh screen using CO-MIL™ brand mill and continued dryingat 50° C. until moisture content is about 3-7%. The dried granules arethen milled through a 40 mesh screen using CO-MIL™ brand mill [QUADRO].

In a separate container, 10.37 g of triacetin and 693.38 g of KOLLICOAT™SR-30D are mixed for 1 hour (solution-A). SURETERIC™ 90G 18507 White isdispersed in 554.65 g of purified water and mixed for 30 minutes(solution-B) using propeller mixer (ARROW™). Solution B is added intoSolution A and mixed for 1 hour using propeller mixer (ARROW™). Thefinal coating is passed through 40 mesh screen. The coating process isperformed in a VECTOR™ FLM-1 fluid bed processor by applying 1,200 g ofcoating solution to 600 g of Morphine sulfate Complex using WURSTERprocess that results in 40% weight gain. The coating conditions arecontrolled at an inlet temperature of 25-35° C., air flow of 10-25 cfm,nozzle pressure of 2-3 kg/cm², accelerator air pressure of 1 kg/cm², andspray rate of 2.5-10 g/min so that uniform coating is achieved. Thecoated morphine resin complex is then placed at 60° C. in VWR™convection oven for 5 hours.

Example 12

It is desirable to reduce the ability of an abuser to “release” theactive drug in a form which is readily injected or otherwiseadministered to achieve a “high”. Thus, the ability to deter immediaterelease of the drug from the composition of the invention by abuse isdesired.

Hybrid Coated Morphine Ion Exchange resin tablets of the inventionprepared in Example 2 were assessed for abuse potential. Each of eightbeakers contained an amount of hybrid coated morphine ion exchange resinequivalent to 200 mg morphine sulfate, i.e., each contained two tabletsprepared as described in Example 2 or ground tablets.

The contents of each beaker were either assessed either “as is” (2soaked tablets per beaker) or “ground” (prior to the placement in thebeaker, tablets were ground and the equivalent of 200 mg morphinesulfate placed in each beaker). For the “ground samples”, the tabletswere ground in a coffee grinder which is commercially available for homeuse for one minute [MR. COFFEE® grinder, Model IDS57], resulting in amixture ranging from powder to granular size.

For each of the “as is” and “ground” tablet samples, the testinginvolved soaking (i) in water with stirring at room temperature, (ii) inwater without stirring at room temperature, (iii) in 40% ethanolsolution with stirring at room temperature, (iv) in 40% ethanol solutionwithout stirring at room temperature. For each sample subjected tostirring, the solution was stirred in a VWR 5-position standardmultiposition stirrer at a setting of 3.

Release from “as is” or “ground” tablets under each of these conditionswas assessed at designated times (10 minutes, 30 minutes, 1 hr, 3 hr,and 6 hr). More particularly, each sample was analyzed for thepercentage (%) of morphine in solution using high performance liquidchromatography (HPLC) against a standard of morphine sulfate. Thestandard consisted of a commercially purchased morphine sulfate, APIversion. For HPLC, a C18 column was set with the flow rate of 1 mL/minwith detector set at 280 nm was used. The mobile phase consists of 20%(v/v) methanol, 0.1% triethylamine (v/v), 0.005M octanesulfonic acidsodium salt, 0.177 M sodium acetate, and pH adjusted to 6.5 with glacialacetic acid.

In the samples subjected to water treatment, the amount of morphinereleased ranged from 2.0% at 10 minutes to 2.5% at 6 hours (ground,unstirred) and ranged from 2.2% at 10 minutes to 7.3% at 6 hours(ground, stirred). The amount of morphine release in the “as is” samplessubjected to water treatment was lower, ranging from 2.9% (10 min) to5.2% (6 hours) for stirred and ranging from 1.6% (10 minutes) to 0.8% (6hours) for unstirred.

The sample subjected to grinding and ethanol with stirring showed thehighest release of active, ranging from 7.2% of morphine being releasedat 10 minutes to 14.8% of morphine being released at 6 hours. The samplesubjected to grinding and ethanol without stirring showed releaseranging from 2.4% morphine release (at 10 minutes) to 5.3% morphinerelease (6 hours).

The “as is” sample subjected to ethanol solution with stirring showed arelease of active ranging from 0.4% (10 minutes) to 5.7% (6 hours);whereas the “as is” sample subjected to ethanol solution withoutstirring showed a release of active ranging from 0.2% (10 minutes) to2.3% (6 hours).

As anticipated, these results showed that when soaked intact (i.e., “asis”), the release of morphine is relatively low. However, when subjectedto abuse, e.g., by grinding, a higher percentage of morphine release isobserved for the tablet of Example 2.

The abuse potential of granules taken from a 100 mg Kadian® extendedrelease capsule was also assessed using the conditions described above.The results of this assessment showed that when the granules from theKadian® extended release capsule were soaked intact (“as is”), arelatively low release of morphine sulfate was observed, with theexception of soaking in 40% ethanol at 6 hours where a significantrelease was observed.

The ground granules from the Kadian® capsule showed a significantlygreater percentage of morphine sulfate released as compared to amount ofactive released from the ground tablet of Example 2 (results describedabove) under the same conditions.

All patents, patent publications, and other publications listed in thisspecification are incorporated herein by reference. While the inventionhas been described with reference to a particularly preferredembodiment, it will be appreciated that modifications can be madewithout departing from the spirit of the invention. Such modificationsare intended to fall within the scope of the appended claims.

1. A coated modified release opioid-ion exchange resin complexcomprising: a pharmaceutically effective amount of an opioid bound to apharmaceutically acceptable ion exchange resin complex; a hybridmodified release coating layer over the resin complex, said hybridcoating comprising: a pH-independent, high tensile strength, waterpermeable, water insoluble, diffusion barrier coating forming componentcomprising polyinylacetate (PVA) and a plasticizer and an entericcoating forming component having pH-dependent solubility in an aqueoussystem which is non-reactive with barrier coating component.
 2. Theopioid-ion exchange resin matrix according to claim 1, wherein theopioid drug is selected from the group consisting of opioid analgesicsdrugs selected from the group consisting of hydrocodone, morphine,hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone,oxymorphone, buprenorphine, fentanyl and derivatives thereof,dipipanone, tramadol, etorphine, dihydroetorphine, butorphanol,levorphanol, or salts thereof or mixtures thereof.
 3. The opioid-ionexchange resin matrix according to claim 1, wherein the opioid ismorphine or morphine sulfate.
 4. The coated opioid-ion exchange resincomplex according to claim 1, wherein the enteric polymer formingcomponent comprises polyvinyl acetate phthalate and at least oneplasticizer.
 5. The coated opioid-ion exchange resin complex accordingto claim 1, wherein the barrier coating forming component and entericpolymer forming component are present in a ratio of about 20:1 to about3:1 wt/wt.
 6. The coated opioid drug-ion exchange resin complexaccording to claim 5, wherein the barrier coating forming component andenteric polymer forming component are present in a ratio of about 6:1 to4:1 wt/wt.
 7. The coated opioid drug-ion exchange resin complexaccording to claim 2, wherein the enteric coating forming componentcomprises a polyinylacetate phthalate, at least one plasticizer, and oneor more selected from the group consisting of a detackifier, alubricant, an alkalizing agent, a viscosity modifier, and an anti-cakingagent.
 8. The coated opioid drug-ion exchange resin complex according toclaim 7, wherein the enteric coating forming component comprises aliquid plasticizer and a solid plasticizer.
 9. The coated opioiddrug-ion exchange resin complex according to claim 9, wherein the liquidplasticizer is citroflex triethylcitrate.
 10. The coated opioid drug-ionexchange resin complex according to claim 9, wherein the solidplasticizer is polyethylene glycol
 3350. 11. The coated opioid drug-ionexchange resin complex according to claim 7, wherein the enteric coatingforming component comprises titanized polyvinylacetate phthalate. 12.The coated opioid drug-ion exchange resin complex according to claim 1,wherein the barrier coating forming component comprises about 70% toabout 95% w/w polyvinyl acetate.
 13. The coated opioid drug-ion exchangeresin complex according to claim 12, wherein the barrier coating formingcomponent comprises PVA, a stabilizer, a surfactant and a plasticizer.14. The coated opioid drug-ion exchange resin complex according to claim13, wherein the plasticizer comprises about 3 to about 10% w/w of solidsin the barrier coating forming component.
 15. The coated opioid drug-ionexchange resin complex according to claim 13, wherein the plasticizer inthe barrier coating forming component is selected from the groupconsisting of dibutyl sebacate, propylene glycol, polyethylene glycol,polyvinyl alcohol, triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate, tributyl citrate, triacetin, Soluphor P, and mixturesthereof.
 16. The coated opioid drug-ion exchange resin complex accordingto claim 15, wherein the plasticizer is triacetin.
 17. The coated opioiddrug-ion exchange resin complex according to claim 13, wherein thestabilizer is a polyvinylpyrrolidone.
 18. The coated opioid drug-ionexchange resin complex according to claim 17, wherein the polyvinylpyrrolidone comprises about 5 to about 10% w/w of the barrier coatingforming component.
 19. The coated opioid drug-ion exchange resin complexaccording to claim 13, wherein the surfactant is sodium lauryl sulfate.20. The opioid-ion exchange resin complex according to claim 1, whereinthe hybrid coating comprises 25% to 50% by weight of the coated complex.21. The opioid-ion exchange resin complex according to claim 20, whereinthe hybrid coating comprises 30% to 45% by weight of the coated complex.22. A solid dose comprising the coated opioid drug-ion exchange resincomplex according to claim 1 and pharmaceutically acceptable excipients,wherein the opioid-ion exchange resin complex is in a matrix with atleast one polymer to form an opioid-drug ion exchange resincomplex-matrix.
 23. The solid dose according to claim 22, wherein the atleast one polymer is selected from the group consisting of a polyvinylacetate polymer, polyvinylpyrrolidone, ethyl cellulose, celluloseacetate, acrylic based polymers or copolymers, cellulose phthalate, andmixtures thereof.
 24. A solid dose modified release morphine formulationcomprising: a pharmaceutically effective amount of morphine bound to apharmaceutically acceptable cationic exchange resin complex; a curedhybrid modified release coating layer over the resin complex, saidhybrid coating comprising a single layer comprising a barrier formingcomponent comprising polyinylacetate (PVA) and a plasticizer and anenteric coating component comprising PVA-phthalate and at least oneplasticizer.
 25. The solid dose modified release morphine formulationaccording to claim 24, wherein the barrier forming component furthercomprises polyvinyl pyrrolidone and sodium laurel sulfate.
 26. The soliddose modified release morphine formulation according to claim 24,wherein the enteric coating component further comprises a liquidplasticizer, a solid plasticizer, and at least one or more of adetackifier, a lubricant, an alkalizing agent, a viscosity modifier, andan anti-caking agent.
 27. The solid dose modified morphine formulationaccording to claim 26, wherein the enteric coating component furthercomprises citroflex triethylcitrate, talc, sodium bicarbonate,polyethylene glycol 3350, stearic acid, sodium alginate, and silica. 28.The solid dose modified release morphine formulation according to claim24, wherein the cured hybrid coating comprises in about of 20:1 byweight to about 6:1 by weight barrier coating component to entericcoating component.
 29. The solid dose modified release morphineformulation according to claim 24, wherein the hybrid coating comprisesabout 30% by weight of the uncoated complex.
 30. The solid dose modifiedrelease morphine formulation according to claim 24, further comprising asolvating agent.
 31. The solid dose modified release morphineformulation according to claim 24, wherein said solid dose is a tablet.32. The solid dose modified release morphine formulation according toclaim 24, further comprising a non-functional coating on the curedhybrid coating layer.
 33. The solid dose modified release morphineformulation according to claim 32, wherein the non-functional coatingcomprises about 2% by weight of the tablet.
 34. The solid dose modifiedrelease morphine formulation according to claim 24, wherein the tabletcomprises a morphine-cation exchange resin complex, at least one filler,at least one lubricant, and at least one diluent.
 35. The solid dosemodified release morphine formulation according to claim 34, wherein thefiller comprises about 1 to 70% by weight of the tablet.
 36. The soliddose modified release morphine formulation according to claim 34,wherein the filler is selected from the group consisting of calciumsilicate, microcrystalline cellulose, lactose and combinations thereof.37. The solid dose modified release morphine formulation according toclaim 34, wherein the lubricant comprises about 0.01% to about 5% w/w ofthe tablet.
 38. The solid dose modified release morphine formulationaccording to claim 34, wherein the lubricant is selected from the groupconsisting of amorphous silica, talc, magnesium stearate, orcombinations thereof.
 39. The solid dose modified release morphineformulation according to claim 34, further comprising a disintegrantcomprising about 1 to about 20% w/w of the tablet.
 40. The solid dosemodified morphine formulation according to claim 39, wherein thedisintegrant is crospovidone.
 41. A method of delivering a sustainedrelease of morphine over a period of at least 12 to 24 hours comprisingorally administering to a subject a solid dose modified release morphineformulation according to claim 34.